7- Azaindole bromination

The medicinal importance of 2-aryltryptamines led Chu and co-workers to develop an efficient route to these compounds (130) via a Pd-catalyzed cross-coupling of protected 2-bromotryptamines 128 with arylboronic acids 129 [137]. Several Suzuki conditions were explored and only a partial listing of the arylboronic acids is shown here. In addition, boronic acids derived from naphthalene, isoquinoline, and indole were successfully coupled with 128. The C-2 bromination of the protected tryptamines was conveniently performed using pyridinium hydrobromide perbromide (70-100%). 2-Phenyl-5-(and 7-)azaindoles have been prepared via a Suzuki coupling of the corresponding 2-iodoazaindoles [19]. 

Bromination proceeds readily with azaindoles to give a monobromo compound, whereas pyrrole and indoles react violently to give poly-halogenated products. 

Fischer attempted the bromination of apoharmine in dilute sulfuric acid at room temperature and obtained a tetrabromo compound, which he did not characterize further. Treatment of l-benzoyl-2,5-dimethyl-4-azaindole with bromine in acetic acid at 25° gave the 3-bromo-l-benzoyl compound in 60% yield. On oxidation with permanganate it gave the same picolinic acid obtained before. Alkaline hydrolysis gave 3-bromo-2,5-dimethyl-4-azaindole (90%), also obtained by direct bromination of 2,5-dimethyl-4-azaindole in 60 % yield. 

Bromination of 7-azaindole in chloroform at 0° gave 3-bromo-7-azaindole in 81 % yield. This compound is stable to treatment with sodium iodide in acetone, like 3-bromoindole, and with hot dilute hydrochloric acid, whereas the indole undergoes hydrolysis. 

Yakhontov et al. also brominated the 4-methyl-7-azaindoles, using bromine in chloroform or bromine-dioxan, obtaining high yields of the brominated 6-H (82%), 6-Cl (82%), and 6-MeO (71%) compounds. The ultraviolet spectra of these compounds agrees with the assignments of the bromine to the 3-position. 

Reactions with electrophilic reagents take place with substitution at C-3 or by addition at the pyridine nitrogen. All the aza-indoles are much more stable to acid than indole (cf. 20.1.1.9), no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards other electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Maniuch and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quatemisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. Acylation at C-3 in all four systems can be carried out at room temperature in the presence of excess aluminium chloride. ... 

I-Alkyl-7-azaisatins. 7-Azaindoles are brominated at C-3 with bromine. Treatment of the products with NBS in DMSO transforms them into the isatins. 

The regioselectivity of bromine-lithium exchange reactions in dibromoindole substrates has been studied by Li [381, 382]. With both 4,7-dibromoindoles (e.g., 145) [382] and 5,7-dibromoindoles (e.g., 146) [381], bromine-lithium exchange occurs preferentially at C7 (Fig. 5) upon treatment with ferf-butyllithium. A similar result was reported recently by Lachance involving the selective chlorine-lithium exchange observed with 6-azaindole 147 [383]. 

Chen and co-workers at Bristol-Meyers Squibb developed a robust process for a-bromination of the pyridine nucleus (299 - 300) on a pharmaceutically important azaindole scaffold (14JOC8757). 

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